Prodrugs of nh-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives

ABSTRACT

The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.

RELATED APPLICATION(S)

This application claims the benefit of U.S. Provisional Application No.61/358,348, filed on Jun. 24, 2010. The entire teachings of the aboveapplication are incorporated herein by reference.

BACKGROUND OF THE INVENTION

(i) Field of the Invention

The present invention relates to prodrugs of lactam, amide, imide,sulfonamide, carbamate, urea, benzamide, and acylaniline containingpharmacophores.

(ii) Background of the Invention.

Drug delivery systems are often critical for the safe and effectiveadministration of a biologically active agent. Perhaps the importance ofthese systems is best realized when patient compliance and consistentdosing are taken under consideration. For instance, reducing the dosingrequirement for a drug from four-times-a-day to a single dose per daywould have significant value in terms of ensuring patient compliance andoptimizing therapy.

Optimization of a drug's bioavailability has many potential benefits.For patient convenience and enhanced compliance it is generallyrecognized that less frequent dosing is desirable. By extending theperiod through which the drug is released, a longer duration of actionper dose is expected. This will then lead to an overall improvement ofdosing parameters such as taking a drug once a day where it haspreviously required four doses per day or dosing once a week or evenless frequently when daily dosing was previously required. Many drugsare presently dosed once per day, but not all of these drugs havepharmacokinetic properties that are suitable for dosing intervals ofexactly twenty-four hours. Extending the period through which thesedrugs are released would also be beneficial.

One of the fundamental considerations in drug therapy involves therelationship between blood levels and therapeutic activity. For mostdrugs, it is of primary importance that serum levels remain between aminimally effective concentration and a potentially toxic level. Inpharmacokinetic terms, the peaks and troughs of a drug's blood levelsideally fit well within the therapeutic window of serum concentrations.For certain therapeutic agents, this window is so narrow that dosageformulation becomes critical.

In an attempt to address the need for improved bioavailability, severaldrug release modulation technologies have been developed. For example,poorly soluble 5,5diphenylimidazolidine-2,4-diones have been derivatizedinto phosphate ester prodrugs to improve solubility. (Stella et al.,U.S. Pat. No. 4,260,769, 1981). Enteric coatings have been used as aprotector of pharmaceuticals in the stomach and microencapsulatingactive agents using proteinaceous microspheres, liposomes orpolysaccharides have been effective in abating enzymatic degradation ofthe active agent. Enzyme inhibiting adjuvants have also been used toprevent enzymatic degradation.

A wide range of pharmaceutical formulations provide sustained releasethrough microencapsulation of the active agent in amides of dicarboxylicacids, modified amino acids or thermally condensed amino acids. Slowrelease rendering additives can also be intermixed with a large array ofactive agents in tablet formulations.

While microencapsulation and enteric coating technologies impartenhanced stability and time-release properties to active agentsubstances these technologies suffer from several shortcomings.Incorporation of the active agent is often dependent on diffusion intothe microencapsulating matrix, which may not be quantitative and maycomplicate dosage reproducibility. In addition, encapsulated drugs relyon diffusion out of the matrix or degradation of the matrix, or both,which is highly dependent on the chemical properties and watersolubility of the active agent. Conversely, water-soluble microspheresswell by an infinite degree and, unfortunately, may release the activeagent in bursts with limited active agent available for sustainedrelease. Furthermore, in some technologies, control of the degradationprocess required for active agent release is unreliable. For example,because an enterically coated active agent depends on pH to release theactive agent and pH and residence time varies, the release rate isdifficult to control.

Several implantable drug delivery systems have utilized polypeptideattachment to drugs. Additionally, other large polymeric carriersincorporating drugs into their matrices are used as implants for thegradual release of drug. Yet another technology combines the advantagesof covalent drug attachment with liposome formation where the activeingredient is attached to highly ordered lipid films.

However there is still a need for an active agent delivery system thatis able to deliver certain active agents which have been heretofore notformulated or difficult to formulate in a sustained release formulationfor release over a sustained period of time and which is convenient forpatient dosing.

There is a generally recognized need for sustained delivery of drugsthat reduces the daily dosing requirement and allows for controlled andsustained release of the parent drug and also avoids irregularities ofrelease and cumbersome formulations encountered with typical dissolutioncontrolled sustained release methods.

SUMMARY OF THE INVENTION

The present invention accomplishes this by extending the period duringwhich a lactam, amide, imide, sulfonamide, carbamate, urea, benzamide,acylaniline, and cyclic amide containing parent drug is released andabsorbed after administration to the patient and providing a longerduration of action per dose than the parent drug itself. In oneembodiment, the compounds suitable for use in the methods of theinvention are derivatives of lactam-, amide-, imide-, sulfonamide-,carbamate-, urea-, benzamide-, acylaniline-, and cyclic amide—containingparent drugs that are substituted at the amide nitrogen or oxygen atomwith prodrug moieties. Preferably, the prodrug moieties are hydrophobicand reduce the polarity and solubility of the parent drug underphysiological conditions.

In one embodiment, the invention provides a prodrug compound of FormulaI, II or III:

or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof;wherein A and B together with the —N(C═X)— or —(SO₂)N— to which they areattached forms a parent drug;

X is —S— or —O—;

R₁ is selected from C(O)OR₂₀, C(O)R₂₀, —C(O)NR₂OR₂₁, —PO₃MY,—P(O)₂(OR₂₀)M and —P(O)(OR₂₀)(OR₂₁);

-   -   wherein each R₂₀ and R₂₁ is independently selected from        hydrogen, aliphatic, substituted aliphatic, aryl or substituted        aryl;    -   Y and M are the same or different and each is a monovalent        cation; or M and Y together is a divalent cation.

The invention further provides a method for sustained delivery of aparent drug by the administration of a conjugate of the parent drug witha labile moiety, wherein the conjugate is represented by Formula I.

BRIEF DESCRIPTION OF THE DRAWING

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawing in which like reference characters refer to thesame parts throughout the different views. The drawing is notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

The FIGURE: Plasma concentration of dehydroaripiprazole after POadministration of (10 mg/Kg) compound 323, 331 and dehydroaripiprazoleto rats.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention provides a prodrug compound of FormulaI, II or III:

or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof;wherein A and B together with the —N(C═X)— to which they are attachedforms a parent drug;

X is —S— or —O—;

R₁ is selected from C(O)OR₂₀, C(O)R₂₀, —C(O)NR₂OR₂₁, —PO₃MY,—P(O)₂(OR₂₀)M and —P(O)(OR₂₀)(OR₂₁);

-   -   wherein each R₂₀ and R₂₁ is independently selected from        hydrogen, aliphatic, substituted aliphatic, aryl or substituted        aryl;    -   Y and M are the same or different and each is a monovalent        cation; or M and Y together is a divalent cation.

The invention further provides a method for sustained delivery of aparent drug by the administration of a conjugate of the parent drug witha labile moiety, wherein the conjugate is represented by Formula I.

In a preferred embodiment, R₁ is selected from —C(O)O—CH₂—OC(O)R₂₁ or—C(O)NH—CH₂—OC(O)R₂₁ or —C(O)O—CH₂—OC(O)N(R₂₁)₂. In a preferredembodiment, R₁ is selected from —C(O)O—CH(CH₃)—OC(O)R₂₁ or—C(O)NH—CH(CH₃)—OC(O)R₂₁ or —C(O)O—CH(CH₃)—OC(O)N(R₂₁)₂. In a preferredembodiment, R₁ is selected from —C(O)O—CH(C₆H₅)—OC(O)R₂₁ or—C(O)NH—CH(C₆H₅)—OC(O)R₂₁ or —C(O)O—CH(C₆H₅)—OC(O)N(R₂₁)₂. In a morepreferred embodiment, R₂₁ is alkyl, substituted alkyl, alkenyl, orsubstituted alkenyl.

In a preferred embodiment, R₁ is selected from —C(O)OR₂₁ or —C(O)NHR₂₁or —C(O)N(R₂₁)₂. In a more preferred embodiment, R₂₁ is alkyl,substituted alkyl, alkenyl, or substituted alkenyl.

In one embodiment, the compounds of the invention having Formula I, IIor III are less soluble, and are preferably at least an order ofmagnitude less soluble, as compared to the parent drug from which theywere derived. In one embodiment, the prodrugs of Formulas I has anaqueous solubility of less than about 0.5 mg/ml, preferably less thanabout 0.1 mg/mL, preferably less than about 0.01 mg/mL, preferably lessthan about 0.001 mg/mL, preferably less than about 0.0001 mg/mL and evenmore preferably less than about 0.00001 mg/ml when solubility ismeasured in a phosphate buffer (pH 7.4) at room temperature.

In a preferred embodiment, a compound of the invention providessustained delivery of the parent drug over hours, days, weeks or monthswhen administered, for example, orally or parenterally, to a subject.For example, the compounds can provide sustained delivery of the parentdrug for at least 8, 12, 24, 36 or 48 hours or at least 4, 7, 15, 30,60, 75 or 90 days or longer. Without being bound by a theory, it isbelieved that the compounds of the invention form an insoluble depotupon parenteral administration, for example subcutaneous, intramuscularor intraperitoneal injection. In one embodiment a prodrug of theinvention may further comprise a sustained release delivery system forproviding additional protection of the prodrug from enzymatic orchemical degradation.

In another embodiment, the invention provides a method for sustaineddelivery of a parent lactam, amide, imide, sulfonamide, carbamate, urea,benzamide, or acylaniline containing drug to a subject in need thereof.Each of these groups comprises an amidic N—H group. The method comprisesadministering to the subject an effective amount of a prodrug formed bysubstituting on the NH group a labile, hydrophobic prodrug moietywherein the prodrug has reduced solubility under physiologicalconditions compared to the parent drug and provides for longer sustainedtherapeutic levels of the parent drug following administration thanobserved levels following administration of the parent drug. In apreferred embodiment, the amidic N—H group has a pKa of about 5 to about22, preferably about 5 to about 21, and preferably about 5 to about 20.

In a preferred embodiment, R₁ is selected from Tables 1-5.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

Wherein each j is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27.

Prodrugs of Lactam, Cyclic Urea, Imide, Carbamate ContainingPharmacophores

In one embodiment, compounds of the present invention are represented byFormula IV and V as illustrated below, or its geometric isomers,enantiomers, diastereomers, racemates, pharmaceutically acceptable saltsco-crystals and solvates thereof:

wherein

represents a single or double bond;X and R₁ are as defined above;Each X₁, X₂, and X₃ is independently selected from absent, —S—, —O—,—S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—, —C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—,—C(R₁₀)(R₁₁)═C(R₁₀)(R₁₁)—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or10;

-   -   wherein each R₁₀ and R₁₁ is independently absent, hydrogen,        halogen, aliphatic, substituted aliphatic, aryl or substituted        aryl; alternatively two R₁₀ and R₁₁ together with the atoms to        which they are attached may form an additional optionally        substituted, 3, 4, 5, 6 or 7 membered ring; and t is 0, 1, 2 or        3.

In one embodiment, compounds of the present invention are represented byFormula VI or VII as illustrated below, and the geometric isomers,enantiomers, diastereomers, racemates, pharmaceutically acceptable saltsand solvates thereof:

wherein

represents a single or double bond;X, X₁, X₂ and R₁ are as defined above;semicircle represents an optionally substituted cycloalkyl,cycloalkenyl, heterocyclyl or aryl containing one, two or three rings;each F₁ and F₂ is independently selected from absent and R₅-A-Cy₁-B-D-;wherein, A is selected from absent, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, —S—,—O—, —S(O)—, —S(O)₂—, —S[C(R₃₀)(R₃₁)]_(u)—, —S(O)[C(R₃₀)(R₃₁)]_(u)—,—S(O)₂[C(R₃₀)(R₃₁)]_(u)—, —O[C(R₃₀)(R₃₁)]_(u)—, —N(R₃₀)—,—N(R₃₀)[C(R₃₁)(R₃₂)]_(u)—, —[C(R₃₀)(R₃₁)]_(u)—, —C(O)[C(R₃₀)(R₃₁)]_(u)—;wherein each u is independently 1, 2, 3, 4, 5, 6 or 7;Cy₁ is absent or an optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, optionally substituted heterocyclyl,optionally substituted aryl or optionally substituted heteroaryl;

B is absent, or a linker;

D is selected from absent, —O—, —NR₃₃, —C(R₃₄)(R₃₅)—, —S—, —S(O),—S(O)₂—, —C(O)—; Each G₁ and G₂ is independently selected from absent,—S—, —O—, —S(O)—, —S(O)₂—, —SC(R₄₀)(R₄₁)—, —S(O)C(R₄₀)(R₄₁)—,—S(O)₂C(R₄₀)(R₄₁)—, —C(O)—, —C(OR₄₀)(R₄₁)—, —OC(R₄₀)(R₄₁)—, —N(R₄₀)—,—C(R₄₀)═C(R₄₁)—, —N(R₄₀)—C(R₄₁)(R₄₂)—, —[C(R₄₀)(R₄₁)]_(U)—;

Each R₃, R₄, R₅, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₄₀, R₄₁, and R₄₂ isindependently selected from absent, hydrogen, halogen, —OR₁₀, —SR₁₀,—NR₁₀R₁₁—, —C(O)R₁₀, optionally substituted aliphatic, optionallysubstituted aryl or optionally substituted heterocyclyl;Alternatively, two R₃ groups together or two R₄ groups together or oneR₃ group with one R₄ group together forms an optionally substitutedring;m and q are independently selected from 0, 1, and 2.

In a preferred embodiment, G₂ is selected from —N— or —C(R₁₀)—.

In a preferred embodiment, the R₅ moiety is an aryl or heteroaryl groupselected from:

wherein R₁₀₀ R₁₀₁, and R₁₀₃ are independently selected from hydrogen,halogen, optionally substituted C₁-C₈ alkyl, optionally substitutedC₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈ alkylamino and optionally substituted C₁-C₈aryl.

In a preferred embodiment, Cy₁ is selected from:

In a preferred embodiment, the bivalent B is a direct bond, a straightchain C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl, C₁-C₁₀ alkoxy,alkoxyC₁-C₁₀alkoxy, C₁-C₁₀ alkylamino, alkoxyC₁-C₁₀alkylamino, C₁-C₁₀alkylcarbonylamino, C₁-C₁₀ alkylaminocarbonyl, aryloxyC₁-C₁₀alkoxy,aryloxyC₁-C₁₀alkylamino, aryloxyC₁-C₁₀alkylamino carbonyl,C₁-C₁₀-alkylaminoalkylaminocarbonyl, C₁-C₁₀alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino,alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino,(N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl,alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl,alkylpiperazino, alkenylaryloxyC₁-C₁₀alkoxy,alkenylarylaminoC₁-C₁₀alkoxy, alkenylaryllalkylaminoC₁-C₁₀alkoxy,alkenylaryloxyC₁-C₁₀alkylamino, alkenylaryloxyC₁-C₁₀alkylaminocarbonyl,piperazinoalkylaryl, heteroarylC₁-C₁₀alkyl, heteroarylC₂-C₁₀alkenyl,heteroarylC₂-C₁₀alkynyl, heteroarylC₁-C₁₀alkylamino,heteroarylC₁-C₁₀alkoxy, heteroaryloxyC₁-C₁₀alkyl,heteroaryloxyC₂-C₁₀alkenyl, heteroaryloxyC₂-C₁₀alkynyl,heteroaryloxyC₁-C₁₀alkylamino and heteroaryloxyC₁-C₁₀alkoxy.

In one embodiment, compounds of the present invention are represented byFormula VIII or VIIIA as illustrated below, or its geometric isomers,enantiomers, diastereomers, racemates, pharmaceutically acceptable saltsand solvates thereof:

wherein R₁, R₃, R₄, G₁, G₂, X, F₂, m and q are as defined above.

In a more preferred embodiment, compounds of the present invention arerepresented by Formula IX or X as illustrated below, or its geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

wherein R₁, R₃, F₂, and q are as defined above.

In a preferred embodiment a compound is selected from Table IX-X. A morepreferred embodiment is a compound from Table IX-X wherein R₁ isselected from Tables 1-4.

TABLE IX-X No Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

In a more preferred embodiment, prodrugs of domperidone are disclosed.(Formula 4 and 11 from Table IX-X). A more preferred embodiment is acompound of Formula 4 from Table IX-X, wherein R₁ is selected fromTable 1. In a more preferred embodiment, a compound of Formula 4 fromTable IX-X, wherein R₁ is selected from Tables 2-4 is disclosed.

In a more preferred embodiment, prodrugs of droperidol are disclosed.(Formula 6 and 13, from Table IX-X). In a more preferred embodiment, acompound of Formula 6 from Table IX-X wherein R₁ is selected from Table1 is disclosed. A more preferred embodiment is a compound of Formula 6from Table IX-X wherein R₁ is selected from Tables 2-4.

In a more preferred embodiment, prodrugs of pimozide are disclosed.(Formula 7 and 14 from Table IX-X). In a more preferred embodiment, acompound of Formula 7 from Table IX-X wherein R₁ is selected from Table1 is disclosed. In a more preferred embodiment, a compound of Formula 7from Table IX-X wherein R₁ is selected from Tables 2-4 is disclosed.

In another embodiment, compounds of the present invention arerepresented by Formula XI or XII as illustrated below, or its geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

wherein R₁, R₃, R₄, X, F₁, G₁, G₂, m and q are as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIA or XIIA as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, R₃, R₄, R₅, R₁₀, R₁₁, A, D, m, and q are as defined above;R₂ is selected from absent, hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—,optionally substituted aliphatic, optionally substituted aryl or aryl oroptionally substituted heterocyclyl;r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;each G₃ and G₄ is independently selected from —N—,—C(R₁₀)—[C(R₁₀)(R₁₁)]_(a)—, wherein a is 0, 1 or 2;

X₂₀ is —C(R₁₀)— or —N—; and

p is selected 0, 1, 2 or 3.

In another embodiment, compounds of the present invention arerepresented by Formula XIB or XIIB as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, R₂, R₃, R₄, R₅, R₁₀, R₁₁, A, D, m, p and q are as definedabove.

In another embodiment, compounds of the present invention arerepresented by Formula XIC or XIIC as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, is as defined above; andw is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

In another embodiment, compounds of the present invention arerepresented by Formula XID or XIID as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X₁, R₁, R₂, R₃, R₅, A, B, D, G₃, G₄, p, q, R₁₀ and R₁₁ are asdefined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIE or XIIE as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, R₁, R₂, R₃, R₄, A, D, G₃, G₄, m, q, r, R₁₀ and R₁₁ are asdefined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIF or XIIF as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, R₁, R₂, D, r, R₁₀ and R₁₁ are as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIG or XIIG as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, is as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIH or XIIH as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, R₁, R₂, R₅, A, D, G₃, G₄ and p, are as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XI-I or XII-I as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, is as defined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIJ or XIIJ as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, R₁, R₂, R₃, R₄, R₅, A, D, G₃, G₄, p, R₁₀ and R₁₁ are asdefined above.

In another embodiment, compounds of the present invention arerepresented by Formula XIK or XIIK as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, is as defined above.

In a preferred embodiment a compound is selected from Table XI-XII. Amore preferred embodiment is a compound from Table XI-XII, wherein R₁ isselected from Table 1-4.

TABLE XI-XII XI-1

XI-2

XI-3

XI-4

XI-5

XI-6

XII-1

XII-2

XII-3

XII-4

XII-5

XII-6

In a more preferred embodiment, prodrugs of aripiprazole are disclosed.(Formula 1 and 7 from Table XI-XII). In a more preferred embodiment, acompound of Formula 1 wherein R₁ is selected from Table 1 is disclosed.In a more preferred embodiment, a compound of Formula 1 wherein R₁ isselected from Tables 2-4 is disclosed.

In a more preferred embodiment, prodrugs of dehydroaripiprazole aredisclosed. (Formula 2 and 8 from Table XI-XII). In a more preferredembodiment, a compound of Formula 2 wherein R₁ is selected from Table 1is disclosed. In a more preferred embodiment, a compound of Formula 2wherein R₁ is selected from tables 2-4 is disclosed.

In a more preferred embodiment, prodrugs of ziprasidone are disclosed.(Formula 3 and 9 from Table XI-XII). In a more preferred embodiment, acompound of Formula 3 wherein R₁ is selected from Table 1 is disclosed.In a more preferred embodiment, a compound of Formula 3 wherein R₁ isselected from Tables 2-4 is disclosed.

In a more preferred embodiment, prodrugs of bifeprunox are disclosed.(Formula 4 and 11 from Table XI-XII). In a more preferred embodiment, acompound of Formula 4 wherein R₁ is selected from Table 1 is disclosed.In a more preferred embodiment, a compound of Formula 4 wherein R₁ isselected from tables 2-4 is disclosed.

Representative compounds according to the invention are those selectedfrom the Tables A-F below and the geometric isomers, enantiomers,diastereomers, racemates, pharmaceutically acceptable salts and solvatesthereof:

TABLE A No. Structure 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

TABLE B No. Structure 100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

TABLE C No. Structure 200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

TABLE D No. Structure 300.

301.

302.

303.

304.

305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315.

316.

317.

318.

319.

320.

321.

322.

322.

323.

324.

325.

326.

327.

328.

329.

330.

331.

332.

333.

334.

335.

336.

337.

338.

339.

340.

341.

342.

343.

344.

TABLE E No. Structure 400.

401.

402.

403.

404.

405.

406.

407.

408.

409.

410.

411.

412.

413.

414.

415.

416.

417.

418.

419.

420.

421.

422.

423.

424.

425.

426.

427.

428.

429.

TABLE F No. Structure 500.

501.

502.

503.

504.

505.

506.

507.

508.

509.

510.

511.

512.

513.

514.

515.

516.

517.

518.

519.

520.

521.

522.

523.

524.

525.

526.

527.

528.

529.

530.

531.

532.

533.

534.

535.

536.

537.

In another embodiment, the invention relates to a compound of Formula LIand LII:

In another aspect of the invention, compounds of Formula LI and LII areselected from Table G:

TABLE G No. Structure 700.

701.

702.

703.

704.

705.

706.

707.

708.

709.

710.

711.

712.

713.

714.

715.

716.

717.

718.

719.

720.

721.

722.

723.

724.

725.

726.

727.

728.

729.

730.

731.

732.

733.

734.

735.

736.

737.

738.

739.

740.

741.

742.

743.

744.

745.

746.

747.

748.

749.

750.

751.

752.

753.

754.

755.

756.

757.

758.

759.

760.

761.

762.

763.

764.

765.

766.

767.

768.

769.

770.

771.

772.

773.

774.

775.

776.

777.

778.

779.

780.

781.

Compounds of Formula IX, X, XI, XII and in particular compounds ofTables A-E are useful for the treatment of neurological and psychiatricdisorders including schizophrenia, mania, anxiety and bipolar disease.These compounds provide sustained release of parent pharmacophores bycleavage of the labile moiety, R₁.

In another embodiment, compounds of the present invention arerepresented by Formula XIII or XIV as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁₀₀, R₁₀₁, R₁₀₂, and R₁₀₃ are independently selected fromabsent, hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionallysubstituted aliphatic, optionally substituted aryl or aryl or optionallysubstituted heterocyclyl;alternatively, two R₁₀₀, and R₁₀₁ together form an optionallysubstituted ring; and

X₁₀₀ is —CH— or —N—.

A preferred embodiment is a compound selected from Table XIII-XIV. Amore preferred embodiment is a compound from Table XIII-XIV wherein R₁is selected from tables 1-4.

TABLE XIII-XIV 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

Prodrugs of Acylanilines

In another embodiment, compounds of the present invention arerepresented by Formula XV or XVI as illustrated below, or its geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

wherein R₁ is as defined above;each R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ is independently selected fromhydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionally substitutedaliphatic, optionally substituted aryl or aryl or optionally substitutedheterocyclyl;alternatively, two or more R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ together forman optionally substituted ring.

A preferred embodiment is a compound selected from Table XV-XVI. A morepreferred embodiment is a compound from Table XV-XVI wherein R₁ isselected from Tables 1-4.

TABLE XV-XVI 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

Thiazolidinones

In another embodiment, compounds of the present invention arerepresented by Formula XVII, XVIII or XIX as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein F₁ and R₁ are as defined above.

A preferred embodiment is a compound of Formula XX, XXI or XXII asillustrated below, or its geometric isomers, enantiomers, diastereomers,racemates, pharmaceutically acceptable salts and solvates thereof:

wherein R₁ is as defined above;Cy₂ is an optionally substituted heterocyclic ring; andX₅ is selected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—,—C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—, —O[C(R₁₀)(R₁₁)]_(v)—,—O[C(R₁₀)(R₁₁)]_(v)O—, —S[C(R₁₀)(R₁₁)]_(v)—, —NR₁₂[C(R₁₀)(R₁₁)]_(v)O—,—NR₁₂[C(R₁₀)(R₁₁)]_(v)S—, —S[C(R₁₀)(R₁₁)]_(v)—, —C(O)[C(R₁₀)(R₁₁)]_(v)—,and —C(R₁₀)(R_(ii))═C(R₁₀)(R_(ii))—; wherein v is 0, 1, 2, 3, 4, 5, 6,7, 8, 9 or 10.

A preferred embodiment is a compound of Formula XXIV as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula XXIV, R₁ is selected fromTables 1-4.

A preferred embodiment is a compound of Formula XXV as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula XXV, R₁ is selected fromTables 1-4.

A preferred embodiment is a compound of Formula XXVI as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula XXV₁, R₁ is selected fromTables 1-4.

A preferred embodiment is a compound of Formula XXVII as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula XXVI₁, R₁ is selected fromTables 1-4.

A preferred embodiment is a compound of Formula XXVIII as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula)(XVII₁, R₁ is selected fromtables 1-4.

A preferred embodiment is a compound of Formula XXIX as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula XXIX, R₁ is selected fromtables 1-4.

A preferred embodiment is a compound of Formula XXX as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula XXX, R₁ is selected from Table1.

A preferred embodiment is a compound of Formula XXXI as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula XXXI, R₁ is selected fromTable 1.

A preferred embodiment is a compound of Formula XXXII as illustratedbelow, or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

In a more preferred embodiment of Formula XXXII, R₁ is selected fromTable 1.

In a preferred embodiment a compound of Formula XX-XXII is selected fromtable XX-XXII below, wherein R₁ is as described above. A more preferredembodiment is a compound of table XX-XXII wherein R₁ is selected fromTables 1-4.

TABLE XX-XXII 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

Thiazolidinedione prodrugs of Formula XVII to XXXII are useful for thetreatment of type 2 diabetes mellitus. Herein provided is a method oftreating type 2 diabetes mellitus by the administration of a prodrug ofFormula XVII to XXXII, in particular a compound of table XX-XXII abovewherein the prodrug provides sustained release of the parent drug. Theparent drug results from the cleavage of the labile R₁ moiety.

In some embodiments, a compound of Formula XXVII is selected from tableH:

TABLE H No. Structure 1000.

1001.

1002.

1003.

1004.

1005.

1006.

1007.

1008.

1009.

1010.

1011.

1012.

1013.

1014.

1015.

1016.

1017.

1018.

1019.

1020.

1021.

1022.

1023.

1024.

1025.

1026.

1027.

1028.

1029.

1030.

1031.

1032.

1033.

1034.

1035.

1036.

1037.

1038.

1039.

1040.

1041.

Barbiturates

In another embodiment, compounds of the present invention arerepresented by Formula) XXXIII-XXXVII as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein, X, X₁, X₂, R₁₀₀, R₁₀₁, and R₁ are as defined above;

X₁₀ is —S or —O.

In a preferred embodiment a compound from Table XXXIII-XXXVII isprovided. A more preferred embodiment is a compound of tableXXXIII-XXXVII wherein R₁ is selected from tables 1-4.

TABLE XXXIII-XXXIV 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

Pyridone Pyrimidone and Pyrimidione Prodrugs

In another embodiment, compounds of the present invention arerepresented by Formula XXXVIII or XXXIX as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein X, R₁, R₃, R₄, m and q are as defined above;

X₁₁ is —N— or —C(R₁₀)—; X₁₂ is —C(O)—, —C(S)—, —C(R₁₀)(R₁₁)— or—C(R₁₀)(OR₁₁)—; and X₁₃ is —O, —S, —N(R₁₀)(R₁₁), —OR₁₀.

A preferred embodiment is a compound selected from table XXXVIII-XXXIX.A more preferred embodiment is a compound from table XXXVIII-XXXIXwherein R₁ is selected from Tables 1-4.

TABLE XXXVIII 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

Prodrugs of Benzamide Pharmacophores

In another embodiment, compounds of the present invention arerepresented by Formula XL or XLI as illustrated below, or its geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

wherein R₁, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ are as defined above.

TABLE XL-XLI  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

Prodrugs of Imide Pharmacophores

In another embodiment, compounds of the present invention arerepresented by Formula XLII, XLIII or XLIV as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts and solvates thereof:

wherein R₁, R₁₀₀, R₁₀₁, X, X₁ and X₂ are as defined above; alternativelyR₁₀₀ and R₁₀₁ together with the atoms to which they are attached form anoptionally substituted 3, 4, 5, 6, or 7 membered ring.

A preferred embodiment is a compound selected from table XLII-XLIV. Amore preferred embodiment is a compound from table XLII_XLIV wherein R₁is selected from Tables 1-4.

TABLE XLII-XLIV XLII-  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

XLIII-  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

XLIV-  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

In another embodiment, compounds of the present invention having theFormula VI or VII is selected from Table VI-VII.

TABLE VI-VII  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

53

Prodrugs of Sulfonamide Pharmacophores

In another embodiment, compounds of the present invention arerepresented by Formula III as illustrated below, or its geometricisomers, enantiomers, diastereomers, racemates, pharmaceuticallyacceptable salts and solvates thereof:

A preferred embodiment is a compound selected from Table III. A morepreferred embodiment is a compound from Table III wherein R₁ is selectedfrom Tables 1-4.

TABLE III  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

59

60

61

62

63

64

65

66

67

68

69

70

71

Chlorothiazide and hydrochlorothiazide compounds of Formula III and inparticular Table III are useful for the treatment of hypertension,congestive heart failure, osteoporosis, symptomatic edema peripheraledema, kidney stones, diabetes, nephrogenic diabetes insipidus,hypercalcaemia, Dent's disease and Meniere's disease. Compounds ofFormula III and Table III provide sustained release of parent drugs bycleavage of the labile R₁ moiety. Compounds of Formula III, for exampleIII-63 to III-71 are useful as prodrugs for the treatment of diabetes.

The invention further relates the sustained delivery of a compound ofFormula XLV or XLVI by the administration of a compound of Formula I-IIIas shown in Scheme I. Upon administration of a compound of FormulaI-III, the labile R₁ moiety may be cleaved off enzymatically, chemicallyor through first phase metabolism giving a compound of Formula XLV orXLVI. Without being bound to any theory, it is postulated that for someof the compounds of Formula I-III, the release of a compound of FormulaXLV or XLVI upon cleavage of the R₁ moiety results in a therapeuticallyactive agent. For example such active ingredient can be aripiprazole,ziprasidone or bifeprunox. In one embodiment, the sustained releasecomprises a therapeutically effective amount of a compound of FormulaXLV or XLVI in the blood stream of the patient for a period of at leastabout 8, preferably at least about 12, more preferably at least about 24and even more preferably at least about 36 hours after administration ofa compound of Formula I-III. In one embodiment, the compound of FormulaXLV or XLVI is present in the blood stream of the patient for a periodselected from: at least 48 hours, at least 4 days, at least one week,and at least one month. In one embodiment, a compound of Formula I-IIIis administered by injection.

Compounds of Formula IX, X, XI, XII, XIII, XIV, XXXIII, XXXIV, XXXV,XXXVI, and XXXVII are useful for the treatment of neurological andpsychological disorders. Neurological and psychiatric disorders include,but are not limited to, disorders such as cerebral deficit subsequent tocardiac bypass surgery and grafting, stroke, cerebral ischemia, spinalcord trauma, head trauma, perinatal hypoxia, cardiac arrest,hypoglycemic neuronal damage, dementia (including AIDS-induceddementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateralsclerosis, ocular damage, retinopathy, cognitive disorders, idiopathicand drug-induced Parkinson's disease, muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, cerebral deficits secondary to prolonged statusepilepticus, migraine (including migraine headache), urinaryincontinence, substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, social phobia, obsessive compulsive disorder, andpost-traumatic stress disorder (PTSD)), mood disorders (includingdepression, mania, bipolar disorders), circadian rhythm disorders(including jet lag and shift work), trigeminal neuralgia, hearing loss,tinnitus, macular degeneration of the eye, emesis, brain edema, pain(including acute and chronic pain states, severe pain, intractable pain,neuropathic pain, inflammatory pain, and post-traumatic pain), tardivedyskinesia, sleep disorders (including narcolepsy), attentiondeficit/hyperactivity disorder, eating disorders and conduct disorder.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g. single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, and substituted or unsubstituted cycloalkyl groupsas described herein.

The term “acyl” refers to a carbonyl substituted with hydrogen, alkyl,partially saturated or fully saturated cycloalkyl, partially saturatedor fully saturated heterocycle, aryl, or heteroaryl. For example, acylincludes groups such as (C₁-C₆) alkanoyl (e.g., formyl, acetyl,propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted saturated aliphatic hydrocarbonradicals/groups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”) preferablyabout 7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about24 carbon atoms (“C₈-C₂₄”), preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkyl groups comprise at about 1 to about 8carbon atoms (“C₁-C₈”) such as about 1 to about 6 carbon atoms(“C₁-C₆”), or such as about 1 to about 3 carbon atoms (“C₁-C₃”).Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,neopentyl and n-hexyl radicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkenyl radicals are “lower alkenyl”radicals having two to about ten carbon atoms (“C₂-C₁₀”) such asethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Preferred loweralkenyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”). The terms“alkenyl”, and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkynyl” refers to linear or branched radicals having at leastone carbon-carbon triple bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkynyl radicals are “lower alkynyl”radicals having two to about ten carbon atoms such as propargyl,1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl. Preferredlower alkynyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”).

The term “cycloalkyl” refers to saturated carbocyclic radicals havingthree to about twelve carbon atoms (“C₃-C₁₂”). The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “cycloalkenyl” refers to partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight chain or branched saturated hydrocarbon chain having thespecified number of carbons atoms. Examples of alkylene groups include,but are not limited to, ethylene, propylene, butylene,3-methyl-pentylene, and 5-ethyl-hexylene.

The term “alkenylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbondouble bond. Alkenylene groups include, but are not limited to, forexample, ethenylene, 2-propenylene, 2-butenylene,1-methyl-2-buten-1-ylene, and the like.

The term “alkynylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbontriple bond. Representative alkynylene groups include, but are notlimited to, for example, propynylene, 1-butynylene,2-methyl-3-hexynylene, and the like.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” refers to alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” refers to heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radical.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty-four carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred alkylthio radicals have alkyl radicalswhich are “lower alkylthio” radicals having one to about ten carbonatoms. Most preferred are alkylthio radicals having lower alkyl radicalsof one to about eight carbon atoms. Examples of such lower alkylthioradicals include methylthio, ethylthio, propylthio, butylthio andhexylthio.

The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” refers to aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” refers to alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty-four carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred aminoalkyl radicals are “loweraminoalkyl” that have alkyl radicals having one to about ten carbonatoms. Most preferred are aminoalkyl radicals having lower alkylradicals having one to eight carbon atoms. Examples of such radicalsinclude aminomethyl, aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The terms “compound” “drug”, and “prodrug” as used herein all includepharmaceutically acceptable salts, co-crystals, solvates, hydrates,polymorphs, enantiomers, diastereoisomers, racemates and the like of thecompounds, drugs and prodrugs having the formulas as set forth herein.

Substituents indicated as attached through variable points ofattachments can be attached to any available position on the ringstructure.

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about management of the disease or disorder toclinically acceptable standards.

“Treatment” or “treating” refers to an approach for obtaining beneficialor desired clinical results in a patient. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, one or more of the following: alleviation of symptoms,diminishment of extent of a disease, stabilization (i.e., not worsening)of a state of disease, preventing spread (i.e., metastasis) of disease,preventing occurrence or recurrence of disease, delay or slowing ofdisease progression, amelioration of the disease state, and remission(whether partial or total).

The term “labile” as used herein refers to the capacity of the prodrugof the invention to undergo enzymatic and/or chemical cleavage in vivothereby forming the parent drug. As used herein the term “prodrug” meansa compounds as disclosed herein which is a labile derivative compound ofa heteroaromatic NH-containing parent drug which when administered to apatient in vivo becomes cleaved by chemical and/or enzymatic hydrolysisthereby forming the parent drug such that a sufficient amount of thecompound intended to be delivered to the patient is available for itsintended therapeutic use in a sustained release manner.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid, gel or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha- (α), beta- (β) and gamma- (γ)cyclodextrins; starches such as corn starch and potato starch; celluloseand its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients such as cocoa butter and suppository waxes; oils suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols such as propylene glycol; esters suchas ethyl oleate and ethyl laurate; agar; buffering agents such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol, and phosphatebuffer solutions, as well as other non-toxic compatible lubricants suchas sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In a preferredembodiment, administration is parenteral administration by injection.

The pharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesuspension or emulsion, such as INTRALIPID®, LIPOSYN® OR OMEGAVEN®, orsolution, in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1,3-butanediol. INTRALIPID® is an intravenousfat emulsion containing 10-30% soybean oil, 1-10% egg yolkphospholipids, 1-10% glycerin and water. LIPOSYN® is also an intravenousfat emulsion containing 2-15% safflower oil, 2-15% soybean oil, 0.5-5%egg phosphatides 1-10% glycerin and water. OMEGAVEN® is an emulsion forinfusion containing about 5-25% fish oil, 0.5-10% egg phosphatides,1-10% glycerin and water. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution, USP and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Additional sustained release in accordance with the invention may beaccomplished by the use of a liquid suspension of crystalline oramorphous material with poor water solubility. The rate of absorption ofthe drug then depends upon its rate of dissolution, which, in turn, maydepend upon crystal size and crystalline form. Alternatively, delayedabsorption of a parenterally administered drug form is accomplished bydissolving or suspending the drug in an oil vehicle. Injectable depotforms are made by forming microencapsule matrices of the drug inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of drug to polymer and the nature of the particular polymeremployed, the rate of drug release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping the drugin liposomes or microemulsions that are compatible with body tissues.

In one preferred embodiment, the formulation provides a sustainedrelease delivery system that is capable of minimizing the exposure ofthe prodrug to water. This can be accomplished by formulating theprodrug with a sustained release delivery system that is a polymericmatrix capable of minimizing the diffusion of water into the matrix.Suitable polymers comprising the matrix include polylactide (PLA)polymers and the lactide/glycolide (PLGA) co-polymers.

Alternatively, the sustained release delivery system may comprisepoly-anionic molecules or resins that are suitable for injection or oraldelivery. Suitable polyanionic molecules include cyclodextrins andpolysulfonates formulated to form a poorly soluble mass that minimizesexposure of the prodrug to water and from which the prodrug slowlyleaves.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

By a “therapeutically effective amount” of a prodrug compound of theinvention is meant an amount of the compound which confers a therapeuticeffect on the treated subject, at a reasonable benefit/risk ratioapplicable to any medical treatment. The therapeutic effect may beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect).

In accordance with the invention, the therapeutically effective amountof a prodrug of the invention is typically based on the targettherapeutic amount of the parent drug. Information regarding dosing andfrequency of dosing is readily available for many parent drugs fromwhich the prodrugs of the invention are derived and the targettherapeutic amount can be calculated for each prodrug of the invention.In accordance with the invention, the same dose of a prodrug of theinvention provides a longer duration of therapeutic effect as comparedto the parent drug. Thus if a single dose of the parent drug provides 12hours of therapeutic effectiveness, a prodrug of that same parent drugin accordance with the invention that provides therapeutic effectivenessfor greater than 12 hours will be considered to achieve a “sustainedrelease”.

The precise dose of a prodrug of the invention depends upon severalfactors including the nature and dose of the parent drug and thechemical characteristics of the prodrug moiety linked to the parentdrug. Ultimately, the effective dose and dose frequency of a prodrug ofthe invention will be decided by the attending physician within thescope of sound medical judgment. The specific therapeutically effectivedose level and dose frequency for any particular patient will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcontemporaneously with the specific compound employed; and like factorswell known in the medical arts.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims. General methodology forthe preparation of lactam compounds can be found in the followingpublications: U.S. Pat. No. 7,160,888; U.S. Pat. No. 5,462,934; U.S.Pat. No. 4,914,094; U.S. Pat. No. 4,234,584; U.S. Pat. No. 4,514,401;U.S. Pat. No. 5,462,934; U.S. Pat. No. 4,468,402; WO 2006/090273 A2; WO2008/150848 A1; WO 2006/112464 A1; WO 2008/132600 A1.

Hexyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(Example 1, Compound 59)

To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction wascooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. Aftera further 10 minutes, hexylchloroformate (1.53 mL, 9.37 mmol) was added.The reaction was held at −78° C. for 2 hours before allowing to warm toroom temperature overnight. The reaction was quenched with saturatedaqueous ammonium chloride solution (30 mL) and extracted with ethylacetate (2×30 mL). The organics were combined, washed with saturatedaqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), driedover MgSO₄ and concentrated. The crude product was purified by columnchromatography on silica eluting with 0 to 3% tetrahydrofuran in ethylacetate. The product was triturated in heptane to remove aliphaticimpurities and then filtered and dried to afford Compound 59 (0.487 g)as a colorless solid. ¹H-NMR (300 MHz, CDCl₃) δ 7.14 (2H, m), 7.07 (1H,d), 6.95 (1H, m), 6.62 (1H, dd), 6.54 (1H, d), 4.38 (2H, t), 3.95 (2H,t), 3.06 (4H, m), 2.89 (2H, t), 2.66 (6H, m), 2.47 (2H, t), 1.90-1.65(6H, m), 1.49-1.30 (6H, m), 0.88 (3H, t). [M+H]⁺=576.2.

Isopropyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(Example 2, Compound 75)

To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction wascooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. Aftera further 10 minutes, isopropylchloroformate (9.37 mL, 1.0 mol intoluene, 9.37 mmol) was added. The reaction was held at −78° C. for 2hours before allowing to warm to room temperature overnight. Thereaction was quenched with saturated aqueous ammonium chloride solution(30 mL) and extracted with ethyl acetate (2×30 mL). The organics werecombined, washed with saturated aqueous sodium hydrogen carbonatesolution (30 mL), brine (30 mL), dried over MgSO₄ and concentrated. Thecrude product was purified by column chromatography on silica elutingwith 1:1 ethyl acetate to dichloromethane to 2% methanol in 1:1 ethylacetate to dichloromethane to give the product. The product wasrecrystallized from isopropanol to remove aliphatic impurities. Theproduct was not sufficiently pure so was purified by columnchromatography eluting with 0 to 10% tetrahydrofuran in ethyl acetate.The product was triturated in heptane and filtered to afford Compound 75(0.593 g) as a colorless solid.

¹H-NMR (300 MHz, CDCl₃) δ 7.16 (2H, m), 7.05 (1H, d), 6.95 (1H, m), 6.60(1H, dd), 6.52 (1H, d), 5.22 (1H, quintet), 3.95 (2H, t), 3.07 (4H, m),2.89 (2H, t), 2.66 (6H, m), 2.47 (2H, t), 1.81 (2H, m), 1.74 (2H, m),1.42 (3H, s), 1.40 (3H, s). [M+H]⁺=534.2.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-N-ethyl-3,4-dihydro-2-oxoquinoline-1(2H)-carboxamide(Example 3, Compound 72)

To a solution of aripiprazole (1.5 g, 3.35 mmol) in dichloromethane (33mL) was added triethylamine (0.56 mL, 4.01 mmol) and ethyl isocyanate(0.53 mL, 6.69 mmol). The reaction was stirred at room temperature for 5days. The reaction was quenched with water and extracted withdichloromethane (3×20 mL). The organics were combined, washed withsaturated aqueous sodium hydrogen carbonate (20 mL) and brine (20 mL),dried over MgSO₄ and concentrated. The product was purified by columnchromatography on silica eluting with 0-3% methanol in 1:1 ethyl acetateto dichloromethane. The product was triturated in heptane to removealiphatic impurities and then filtered and dried. The material wasdissolved in ethyl acetate and washed with saturated aqueous sodiumhydrogen carbonate (6×15 mL) to afford Compound 72 (0.482 g) as a pinksolid.

¹H-NMR (300 MHz, CDCl₃) δ 8.44 (1H, t), 7.14 (2H, m), 7.05 (1H, d), 6.94(2H, m), 6.65 (1H, dd), 3.96 (2H, t), 3.43 (2H, quintet), 3.07 (4H, m),2.79 (2H, m), 2.67 (6H, m), 2.47 (2H, t), 1.80 (2H, m), 1.69 (2H, m),1.26 (3H, t). [M+H]⁺=519.2.

N-benzyl-7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxamide(Example 4, Compound 79)

To a solution of aripiprazole (1.5 g, 3.35 mmol) in dichloromethane (33mL) was added triethylamine (0.56 mL, 4.01 mmol) and benzyl isocyanate(0.82 mL, 6.69 mmol). The reaction was stirred at room temperature for48 hours. The reaction was quenched with water and extracted withdichloromethane (3×20 mL). The organics were combined, washed with brine(20 mL), dried over MgSO₄ and concentrated. The residue was purified bycolumn chromatography on silica eluting with 0-10% tetrahydrofuran inethyl acetate. The product was triturated in heptane to remove aliphaticimpurities and then filtered and dried to afford Compound 79 (0.575 g)as a colorless solid.

¹H-NMR (300 MHz, CDCl₃) δ 8.90 (1H, t), 7.44-7.28 (5H, m), 7.15 (2H, m),7.05 (1H, d), 6.97 (2H, m), 6.66 (1H, dd), 4.60 (2H, d), 3.96 (2H, t),3.07 (4H, m), 2.81 (2H, m), 2.67 (6H, m), 2.48 (2H, t), 1.81 (2H, m),1.69 (2H, m). [M+H]⁺=581.2.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2-yldibenzylcarbamate (Example 5, Compound 242)

A mixture of aripiprazole (1.5 g, 3.3 mmol), dibenzylcarbamoyl chloride(1.74 g, 6.7 mmol) silver carbonate (3.75 g, 13.4 mmol) and2-methyltetrahydrofuran (30 mL) was heated at reflux for 4 days. Thereaction mixture was cooled, diluted with ethyl acetate and water, andthen filtered through celite. The organic phase was separated, driedover MgSO₄ and evaporated. The residue obtained was further purified onsilica eluting with ethyl acetate/tetrahydrofuran to give afterevaporation of the major product containing fractions, Compound 80 (1.02g) was a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.44-7.21 (m, 8H), 7.20-7.10 (m, 4H), 7.04 (d,1H), 7.00-6.93 (m, 1H), 6.57 (dd, 1H), 6.40 (d, 1H), 4.80 (d, 1H), 4.54(d, 1H), 4.35 (d, 1H), 4.26 (d, 1H), 3.90-3.81 (m, 1H), 3.74-3.67 (m,1H), 3.15-3.03 (m, 4H), 2.92-2.80 (m, 2H), 2.75-2.60 (m, 6H), 2.65 (t,2H), 2.84-2.63 (m, 4H). [M+H]⁺=671.3.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2-yldiethylcarbamate (Example 6, Compound 234)

Compound 51 was synthesized in a similar manner to Compound 80, (0.80 g)as a yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.17-7.12 (2H, m), 7.07 (d,1H), 7.99-7.92 (m, 1H), 6.57 (dd, 1H), 6.39 (dd, 1H), 4.00-3.85 (m, 2H),3.76-3.62 (m, 2H), 3.54-3.40 (m, 2H), 3.25-3.15 (m, 2H), 3.12-3.01 (m,4H), 2.92 (t, 2H), 2.76-2.56 (m, 6H), 2.47 (t, 2H), 1.84-1.60 (m, 4H),1.31 (t, 3H), 1.10 (t, 3H). [M+H]⁺=547.2.

Methyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(Example 7, Compound 74)

To a solution of diisopropylamine (0.99 mL, 7.02 mmol) in2-methyltetrahydrofuran (33 mL) at −5° C. was added n-BuLi (2.67 mL, 2.5M in hexanes, 6.69 mmol) slowly. After 20 minutes, the reaction wascooled to −78° C. and aripiprazole (1.50 g, 3.34 mmol) was added. Aftera further 10 minutes, methylchloroformate (0.65 mL, 8.36 mmol) wasadded. The reaction was held at −78° C. for 2 hours before allowing towarm to room temperature. After 2 hours the reaction was quenched withsaturated aqueous ammonium chloride solution (30 mL) and extracted withethyl acetate (2×30 mL). The organics were combined, washed withsaturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30mL), dried over MgSO₄ and concentrated. The crude product was purifiedby column chromatography on silica eluting with 1:1 ethyl acetate todichloromethane to 10% methanol in 1:1 ethyl acetate to dichloromethaneto give the product. The product was triturated in heptane to removealiphatic impurities and then filtered to afford Compound 74 (0.824 g)as a colorless solid.

¹H-NMR (300 MHz, CDCl₃) δ 7.15 (2H, m), 7.06 (1H, d), 6.95 (1H, m), 6.63(1H, dd), 6.56 (1H, d), 3.99 (3H, s), 3.95 (2H, t), 3.07 (4H, m), 2.89(2H, t), 2.67 (6H, m), 2.48 (2H, t), 1.81 (2H, m), 1.72 (2H, m).[M+H]⁺=506.1.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-isobutyryl-3,4-dihydroquinolin-2(1H)-one(Example 8, Compound 16)

To a solution of diisopropylamine (1.3 mL, 8.9 mmol) in tetrahydrofuran(25 mL) at 78° C. was added n-BuLi (2.2M in hexanes, 4.1 mL, 8.9 mmol).The reaction mixture was warmed to 0° C. and after 10 min was re-cooledto 78° C. and aripiprazole (2.0 g, 4.5 mmol) added. The reaction mixturewas stirred for 30 min and then isobutyryl chloride (0.7 mL, 6.7 mmol)added. After 2 h the reaction mixture was warmed to room temperature andstirred for 1 h. A second reaction was carried out under exactly thesame conditions and the two reactions were combined. This mixture waswashed with water, dried over MgSO₄, filtered and evaporated. Theresidue was dissolved in diethyl ether and 4M HCl in diethyl ether addedto form a precipitate. The mother liquor was decanted and the residualgum was washed with diethyl ether. The gum was then partitioned betweenethyl acetate and saturated sodium bicarbonate, and the organic layerseparated. After drying over MgSO₄ and evaporation, the residue wasfurther purified on silica eluting with 1:1:0.1 dichloromethane/ethylacetate/methanol to give Compound 16 (1.3 g) as a yellow solid. ¹H-NMR(300 MHz, CDCl₃) δ 7.16-7.13 (m, 2H), 7.08 (d, 1H), 6.98-6.92 (m, 1H),6.65-6.59 (m, 2H), 3.93 (t, 2H), 3.48 (dt, 1H), 3.12-3.01 (m, 4H), 2.86(dd, 1H), 2.72-2.59 (m, 6H), 2.47 (t, 2H), 1.84-1.64 (m, 4H), 1.25 (d,6H). [M+H]⁺=518.2.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2-ylpivalate (Example 9, Compound 216)

To a stirred solution of aripiprazole (0.1 g, 0.223 mmol) in pyridine (1mL) at 0° C. was added pivaloyl chloride (0.055 mL, 0.446 mmol). Afterstirring at 0° C. for 5 minutes the reaction was allowed to warm to roomtemperature. After a further 5 minutes the temperature was increased to50° C. for approximately 19 hours. The reaction was allowed to cool toroom temperature. The reaction was repeated in a similar manner using ofaripiprazole (1.75 g, 3.90 mmol). The two reaction mixtures werecombined and quenched with approximately methanol (5 mL). The majorityof the pyridine was removed in vacuo and the residue partitioned betweendichloromethane (30 mL) and saturated NaHCO₃ solution (30 mL). Theaqueous phase was extracted with dichloromethane (2×30 mL) and thecombined organic extracts washed with brine (20 mL) and dried overMgSO₄. After filtration, the volatiles were removed (toluene andmethanol/dichloromethane azeotrope) and the residue purified by silicachromatography eluting first with dichloromethane followed by ethylacetate/dichloromethane/methanol (1:1:0.04) to give the title compound(1.19 g, 54%).

¹H NMR (CDCl₃, 300 MHz) δ 7.13-7.17 (m, 2H), 7.09 (d, 1H), 6.99-6.92 (m,1H), 6.57 (dd, 1H), 6.24 (d, 1H), 3.90 (t, 2H), 3.2-3.0 (m, 4H),2.94-2.83 (m, 2H), 2.78-2.4 (m, 8H), 1.85-1.45 (m, 4H), 1.3 (s, 9H); m/z(M⁺H) 532.26.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-hexanoyl-3,4-dihydroquinolin-2(1H)-one(Example 10, Compound 4)

To a stirred solution of diisopropylamine (1.26 mL, 8.92 mmol) in2-methyltetrahydrofuran (40 mL) at ⁻7° C. was added 1.47 M butyl lithiumin hexanes (6.07 mL, 8.92 mmol) dropwise keeping the temperature between0° C. and 5° C. After stirring at ⁻7° C. for 20 minutes the reaction wascooled to ⁻78° C. A suspension of aripiprazole (2 g, 4.46 mmol) in2-methyltetrahydrofuran (40 mL) was added to the lithiumdiisopropylamide (LDA) solution keeping the temperature below ⁻65° C.After 10 minutes hexanoic anhydride (2.58 mL, 11.15 mmol) was addeddropwise and the reaction stirred at ⁻78° C. under argon gas. After 2.5hours the reaction was allowed to warm to room temperature (removal ofbath). After a further 40 minutes the reaction was quenched withsaturated aqueous NH₄Cl (50 mL) and diluted with ethyl acetate (100 mL).The aqueous layer was extracted with ethyl acetate (2×50 mL) and thecombined organics washed with water (50 mL), saturated aqueous NaHCO₃(3×50 mL), brine (50 mL) and dried over MgSO₄. After filtration, thevolatiles were removed. The crude mixture was purified by silicachromatography eluting with 1% methanol (1:1 ethylacetate/dichloromethane). This material was further purified bypartitioning between ethyl acetate (50 mL) and sat. aqueous NaHCO₃ (50mL). The organic layer was washed with sat. aqueous NaHCO₃ (2×50 mL),brine (50 mL) and dried over MgSO₄. After filtration, the volatiles wereremoved to give Compound 4, 0.95 g.

¹H-NMR (300 MHz, CDCl₃) δ 7.18-7.12 (2H, m), 7.12-7.05 (1H, m),6.99-6.92 (1H, m), 6.81 (1H, d), 6.66 (1H, dd), 3.95 (2H, t), 3.13-3.01(4H, bs), 2.97 (2H, t), 2.87-2.78 (2H, m), 2.74-2.57 (6H, m), 2.48 (2H,t), 1.87-1.64 (6H, m), 1.43-1.29 (4H, m), 0.90 (3H, m). m/z [M+H] 546.1.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-dodecanoyl-3,4-dihydroquinolin-2(1H)-one(Example 11, Compound 7)

Compound 7 was synthesized in a similar manner to Compound 4 in Example10.

¹H-NMR (300 MHz, CDCl₃) δ 7.18-7.12 (2H, m), 7.12-7.05 (1H, m),6.99-6.92 (1H, m), 6.81 (1H, d), 6.65 (1H, dd), 3.95 (2H, t), 3.17-3.01(4H, bs), 2.97 (2H, t), 2.88-2.78 (2H, m), 2.75-2.56 (6H, m), 2.49 (2H,bt), 1.87-1.56 (6H, m), 1.45-1.17 (16H, m), 0.87 (3H, t) m/z [M+H]629.9.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl hexylcarbonate (Example 12, Compound 328)

To a mixture of dehydro-aripiprazole (1.5 g, 3.4 mmol), potassiumtert-butoxide (0.75 g, 6.7 mmol) and 2-methyltetrahydrofuran (30 mL) at0° C. was added hexyl chloroformate (1.32 mL, 8.1 mmol). The reactionmixture was stirred for 2 h, allowed to self warm to room temperatureand stirred for a further 4 h. The reaction mixture was then dilutedwith water and extracted with ethyl acetate. The organic phase was driedover MgSO₄, filtered and evaporated. The residue was further purified onsilica eluting with ethyl acetate/tetrahydrofuran and the major productcontaining fractions evaporated to give a yellow solid. This wastriturated in heptane (30 mL) for 2.5 h, filtered and dried to giveCompound 328 (1.55 g) as a white solid.

¹H-NMR (300 MHz, CDCl₃) δ 8.15 (d, 1H), 7.71 (d, 1H), 7.32 (d, 1H),7.21-7.12 (m, 3H), 7.09 (d, 1H), 6.97-6.91 (m, 1H), 4.29 (t, 1H), 4.13(t, 1H), 3.12-3.01 (m, 4H), 2.73-2.55 (m, 4H), 2.50 (t, 2H), 1.95-1.85(m, 2H), 1.82-1.70 (m, 4H), 1.50-1.28 (m, 6H), 0.94-0.86 (m, 3H).[M+H]⁺=574.2.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-ylisopropyl carbonate (Example 13, Compound 323)

Compound 323 was synthesized in a similar manner as Compound 328 inExample 12.

¹H-NMR (300 MHz, CDCl₃) δ 8.14 (d, 1H), 7.70 (d, 1H), 7.32 (d, 1H),7.20-7.12 (m, 3H), 7.07 (d, 1H), 6.97-6.91 (m, 1H), 5.16-4.98 (m, 1H),4.13 (t, 2H), 3.11-3.02 (m, 4H), 2.72-2.59 (m, 4H), 2.50 (t, 2H),1.94-1.84 (m, 2H), 1.80-1.68 (m, 2H), 1.40 (d, 6H). [M+H]⁺=532.1.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yldiethylcarbamate (Example 14, Compound 334)

A mixture of dehydro-aripiprazole (1.50 g, 3.36 mmol), triethylamine(1.03 mL, 7.39 mmol), diethyl carbamoyl chloride (1.02 mL) were combinedin tetrahydrofuran (30 mL). This was then heated to 100° C. for 6 hoursby microwave. The reaction was quenched with water (50 mL) and extractedwith dichloromethane (2×100 mL). The combined organics were dried(MgSO₄) and concentrated. The crude product was purified by columnchromatrography on silica eluting with ethyl acetate to 20%tetrahydrofuran/ethyl acetate to give the product. The product was thentriturated with heptane to remove aliphatic impurities and then dried togive Compound 334 (1.54 g) as a light brown oil.

¹H-NMR (300 MHz, CDCl₃) δ 8.10 (1H, d), 7.69 (1H, d), 7.31 (1H, d),7.16-7.07 (4H, m), 6.99-6.92 (1H, m), 4.12 (2H, t), 3.54-3.39 (4H, 2×q),3.12-2.96 (4H, br s), 2.78-2.54 (4H, br s), 2.50 (2H, t), 1.97-1.62 (4H,m), 1.32-1.16 (6H, 2×t). [M+H]⁺=545.2.

N,N-diethyl-7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)-carboxamide(Example 15, Compound 150)

Compound 334 was synthesized as described above. Compound 334 (2.17 g,3.99 mmol) was dissolved in pyridine (10 mL) and heated in the microwaveto 175° C. for 5 hours. The reaction was diluted with ethyl acetate (10mL) and concentrated, co-evaporating with toluene (3×5 mL). The productwas purified by column chromatography on silica eluting with 10 to 30%tetrahydrofuran in ethyl acetate to provide Compound 150 (0.81 g) as ayellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.64 (1H, d), 7.45 (1H, d), 7.16 (2H, m), 6.96(1H, m), 6.89 (1H, dd), 6.54 (1H, d), 6.47 (1H, d), 4.04 (2H, m), 3.78(1H, m), 3.57 (1H, m), 3.28-3.00 (6H, m), 2.66 (4H, m), 2.49 (2H, m),1.85 (2H, m), 1.72 (2H, m), 1.39 (3H, t), 1.08 (3H, t). [M+H]⁺=545.2.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yldibenzylcarbamate (Example 16, Compound 342)

To a solution of dibenzylcarbamoyl chloride (1.7 g, 6.7 mmol) inpyridine (15 mL) was added dehydro-aripiprazole (1.5 g, 3.4 mmol) andthe reaction mixture heated at reflux for 4 h. The reaction mixture wasconcentrated and the residue co-evaporated with toluene (×3). Theresidue was dissolved in ethyl acetate (ethyl acetate), washed withwater and dried over MgSO₄. After evaporation the residue was furtherpurified on silica eluting with ethyl acetate and after drying gaveCompound 342 (0.71 g) as a white solid.

¹H-NMR (300 MHz, CDCl₃) δ 8.13 (d, 1H), 7.70 (d, 1H), 7.42-7.29 (m,11H), 7.20-7.08 (m, 4H), 7.00-6.92 (m, 1H), 4.64 (s, 2H), 4.56 (s, 2H),4.14 (t, 2H), 3.15-3.02 (m, 4H), 2.74-2.60 (m, 4H), 2.58-2.48 (m, 2H),1.98-1.88 (m, 2H), 1.83-1.70 (m, 2H). [M+H]⁺=669.1.

N,N-dibenzyl-7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinoline-1(2H)-carboxamide(Example 17, Compound 179)

A solution of Compound 342 (0.94 g, 1.4 mmol) in pyridine (10 mL) washeated in a microwave at 175° C. for 10 h. The reaction mixture wasevaporated and then co-evaporated with toluene. The residue was furtherpurified on silica eluting with ethyl acetate to give after evaporationof the product containing fractions, Compound 179 (0.36 g) as a yellowoil.

¹H-NMR (300 MHz, CDCl₃) δ 7.65 (1H, d), 7.51 (2H, d), 7.39 (5H, m), 7.23(2H, m), 7.16 (4H, m), 6.96 (1H, m), 6.77 (1H, dd), 6.50 (1H, d), 6.39(1H, s), 4.89 (1H, d), 4.64 (1H, d), 4.27 (2H, d), 3.85 (1H, m), 3.65(1H, m), 3.10 (4H, m), 2.68 (4H, m), 2.52 (2H, m), 1.79 (2H, m), 1.72(2H, m). [M+H]⁺=669.1.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl diethylphosphate (Example 18, Compound 331)

To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) indichloromethane (25 ml) was added N,N-dimethyl formamide (1 drop)followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours thereaction mixture was concentrated in vacuo. The residue was dissolved in2-methyltetrahydrofuran (5 mL) and added to a suspension ofdehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92g, 8.17 mmol) in 2-methyltetrahydrofuran (35 mL) at 0° C. under argongas, then allowed to gradually warm to room temperature. After stirringovernight the reaction was quenched with water (25 mL) and 28% aq NH₃(15 mL) and stirred for 10 minutes. The reaction mixture was thenextracted with ethyl acetate (2×40 mL). The combined organics werewashed with water (50 mL) and brine (50 mL) then dried (MgSO₄) andconcentrated in vacuo. The crude mixture was purified by columnchromatography eluting with 5% methanol (1:1 ethylacetate/dichloromethane) to give the product. The ¹H-NMR showed minorimpurities still present (impurities not observed by LCMS). Variousfurther purifications were attempted but failed to remove theseimpurities.

¹H-NMR (300 MHz, CDCl₃) δ 8.04 (1H, d), 7.65 (1H, d), 7.44-7.10 (14H,m), 6.95 (2H, m), 5.33 (4H, m), 4.09 (2H, t), 3.06 (4H, m), 2.65 (4H,m), 2.50 (2H, t), 1.90 (2H, m), 1.74 (2H, m). [M+H]⁺ 707.8.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl dibenzylphosphate (Example 19, Compound 322)

To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) indichloromethane (25 ml) was added dimethyl formamide (1 drop) followedby oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reactionmixture was concentrated in vacuo. The residue was dissolved in2-methyltetrahydrofuran (5 mL) and added to a suspension ofdehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92g, 8.17 mmol) in 2-methyltetrahydrofuran (35 mL) at 0° C. under Ar (g)then allowed to gradually warm to room temperature. After stirringovernight the reaction was quenched with water (25 mL) and 28% aq NH₃(15 mL) and stirred for 10 minutes. The reaction mixture was thenextracted with ethyl acetate (2×40 mL). The combined organics werewashed with water (50 mL) and brine (50 mL) then dried (MgSO₄) andconcentrated in vacuo. The crude mixture was purified by columnchromatography eluting with 5% methanol (1:1 ethylacetate/dichloromethane) to give the product. The ¹H-NMR showed minorimpurities still present (impurities not observed by LCMS). Variousfurther purifications were attempted but failed to remove theseimpurities.

¹H-NMR (300 MHz, CDCl₃) δ 8.04 (1H, d), 7.65 (1H, d), 7.44-7.10 (14H,m), 6.95 (2H, m), 5.33 (4H, m), 4.09 (2H, t), 3.06 (4H, m), 2.65 (4H,m), 2.50 (2H, t), 1.90 (2H, m), 1.74 (2H, m). [M+H]⁺ 707.8.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl pivalate(Example 20, Compound 316)

To a solution of dehydro-aripiprazole (1.2 g, 2.7 mmol) indichloromethane (30 mL) was added pyridine (1 mL), followed by pivaloylchloride (0.66 mL, 5.4 mmol). The reaction mixture was stirred for 20hours, then washed with water and dried over MgSO₄. After evaporationthe residue was co-evaporated with toluene and then further purified onsilica eluting with ethyl acetate. After evaporation of the productcontaining fraction, Compound 316 (0.53 g) was obtained as a colourlessoil.

¹H-NMR (300 MHz, CDCl₃) δ 8.12 (d, 1H), 7.70 (d, 1H), 7.34 (d, 1H),7.20-7.11 (m, 3H), 7.00-6.92 (m, 2H), 4.12 (t, 2H), 3.18-3.02 (m, 4H),2.77-2.45 (m, 6H), 1.95-1.85 (m, 2H), 1.83-1.72 (m, 2H), 1.42 (s, 9H).[M+H]⁺ 530.1.

Acetoxymethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(Example 21, Compound 87)

The reactions were carried out in 2×1 g batches side by side.

To a suspension of aripiprazole (2 g, 4.46 mmol) in2-methyltetrahydrofuran (40 mL) was added NaH (357 mg, 8.92 mmol). After20 minutes, further 2-methyltetrahydrofuran (20 mL) was added to aidstirring. Chloromethyl chloroformate (1.19 mL, 13.38 mmol) was thenadded and the reaction stirred for 2 days. The reactions were combinedfor work up. The reaction was cooled to 0° C., diluted with ethylacetate (50 mL) and quenched with aqueous saturated NaHCO₃ solution (50mL). The reaction was extracted with ethyl acetate (3×50 mL) and thecombined organics washed with brine (100 mL), then dried (MgSO₄) andconcentrated to give chloromethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(crude yield 2.59 g) as 3:2 mixture of product/aripiprazole. The productwas not purified due to instability during silica chromatography and sotaken onto the next step crude.

Synthesis of Compound 87

To a solution of chloromethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(1.20 g, 2.22 mmol) in dimethyl formamide (20 mL) was added cesiumacetate (639 mg, 3.33 mmol). The reaction was then stirred at ambienttemperature overnight. The reaction was diluted with ethyl acetate (50mL) and quenched with water/brine (1:1, 50 mL). The reaction wasextracted with ethyl acetate (3×50 mL). The combined organics werewashed with water (50 mL) then brine (50 mL) and dried (MgSO₄) andconcentrated. The crude product was purified by column chromatography onsilica eluting with 0-10% tetrahydrofuran/dichloromethane with 1% Et₃Nto give the product which required further purification. The product waspurified by column chromatography on silica eluting with 0.5% Et₃N/ethylacetate to give acetoxymethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate,Compound 87 (243 mg, 19% over 2 steps).

¹H-NMR (300 MHz, CDCl₃) δ 7.17-7.08 (3H, m), 6.99-6.89 (1H, m),6.66-6.58 (2H, m), 5.95 (2H, s), 3.96 (2H, t), 3.12-3.01 (4H, m),2.89-2.85 (2H, m), 2.69-2.65 (6H, m), 2.50-2.45 (2H, m), 2.17 (3H, s),1.86-1.59 (4H, m). [M+H]⁺=564.17.

Butyryloxymethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(Example 22, Compound 88)

To a solution of chloromethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(1.20 g, 2.22 mmol) in dimethyl formamide (20 mL) was added butyric acid(0.30 mL, 3.33 mmol) followed by cesium carbonate (542 mg, 1.67 mmol).The reaction was then stirred at ambient temperature overnight. Thereaction was diluted with ethyl acetate (50 mL) and quenched withwater/brine (1:1, 50 mL). The reaction was extracted with ethyl acetate(3×50 mL). The combined organics were washed with water (50 mL) thenbrine (50 mL) and dried (MgSO₄) and concentrated. The crude product waspurified by column chromatography on silica eluting with 010%tetrahydrofuran/dichloromethane with 1% Et₃N to give the product whichrequired further purification. The product was purified by columnchromatography on silica eluting with 0.51.5% Et₃N/ethyl acetate to givebutyryloxymethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate,Compound 88 (348 mg, 26% over 2 steps).

¹H-NMR (300 MHz, CDCl₃) δ 7.17-7.07 (3H, m), 7.01-6.89 (1H, m),6.66-6.58 (2H, m), 5.97-5.92 (2H, m), 3.96 (2H, t), 3.07-2.99 (4H, m),2.89-2.84 (2H, m), 2.70-2.58 (6H, m), 2.51-2.37 (4H, m), 1.86-1.61 (6H,m), 0.96 (3H, m). [M+H]⁺=592.28.

Palmitoyloxymethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(Example 23, Compound 89)

Synthesis of chloromethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

To a suspension of aripiprazole (1 g, 2.23 mmol) in2-methyltetrahydrofuran (20 mL) was added NaH (178 mg, 4.46 mmol). After1 hour, a further of NaH (178 mg) was added. The reaction was stirred atambient temperature overnight then heated to reflux for 3 hours. Thereaction was cooled to room temperature and chloromethyl chloroformate(0.60 mL, 6.69 mmol) was then added and the reaction stirred for 2hours. The reaction was cooled to 0° C., diluted with ethyl acetate (20mL) and quenched with aqueous saturated NaHCO₃ solution (20 mL). Thereaction was extracted with ethyl acetate (3×20 mL) and the combinedorganics washed with brine (50 mL), then dried (MgSO₄) and concentratedto give chloromethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(crude yield 1.54 g) as a 2:1 mixture of product/aripiprazole. Theproduct was taken onto the next step crude.

Synthesis of Compound 89

To a solution of chloromethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(1.16 g, 2.14 mmol) in dimethyl formamide (20 mL) was added palmiticacid (825 mg, 3.22 mmol) and cesium carbonate (524 mg, 1.61 mmol). Thereaction was heated to 60° C. for 5 hours then allowed to cool to roomtemperature. The reaction was diluted with ethyl acetate (20 mL) andwashed with 1:1 water/brine (3×40 mL). The organics were filtered toremove a white precipitate then dried (MgSO₄) and concentrated. Thecrude product was purified by column chromatography on silica elutingwith 0.5% Et₃N/ethyl acetate to give palmitoyloxymethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate,Compound 89 (548 mg, 32% over 2 steps). The material was determined tobe 83% pure by LCMS.

¹H-NMR (300 MHz, CDCl₃) δ 7.17-7.07 (3H, m), 6.99-6.93 (1H, m),6.67-6.59 (2H, m), 5.96-5.91 (2H, m), 3.96 (2H, t), 3.11-3.03 (4H, m),2.92-2.83 (2H, m), 2.70-2.65 (6H, m), 2.52-2.38 (4H, m), 1.83-1.57 (6H,m), 1.35-1.15 (24H, m), 0.87 (3H, t). [M+H]⁺=760.48.

1-(butyryloxy)ethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate)(Example 24, Compound 90)

Synthesis of 1-chloroethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

To a suspension of aripiprazole (2.0 g, 4.46 mmol) in2-methyltetrahydrofuran (50 mL) was added NaH (357 mg, 8.92 mmol). Thereaction was stirred overnight at room temperature then chloroethylchloroformate (1.46 mL, 13.38 mmol) was added. Further2-methyltetrahydrofuran (10 mL) was added to aid stirring. The reactionwas stirred overnight at room temperature. The reaction was cooled to 0°C., diluted with ethyl acetate (50 mL) and quenched with aqueoussaturated NaHCO₃ (50 mL). The reaction was extracted with ethyl acetate(3×50 mL). The combined organics were dried (MgSO₄) and concentrated togive 1-chloroethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(crude yield 2.22 g) as a 3:2 mixture of aripiprazole/product. Theproduct was taken onto the next step without purification.

Synthesis of Compound 90

1-chloroethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(2.0 g, 3.60 mmol) was stirred with butyric acid (1.0 mL, 10.81 mmol)and ethyldiisopropylamine (0.94 mL, 5.41 mmol) at 50° C. for 48 hours.The reaction was diluted with diethyl ether (20 mL) and quenched withaqueous saturated NaHCO₃ (40 mL). The reaction was extracted with ethylacetate (2×50 mL) and the combined organics were washed with water (50mL), brine (50 mL) then dried (MgSO₄). The crude product was purified bycolumn chromatography on silica eluting with 0.5% Et₃N/ethyl acetate togive 1-(butyryloxy)ethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate,Compound 90 (628 mg, 23% over 2 steps).

¹H-NMR (300 MHz, CDCl₃) δ 7.18-6.89 (5H, m), 6.67-6.58 (2H, m),4.01-3.93 (2H, m), 3.11-2.99 (4H, m), 2.94-2.83 (2H, m), 2.69-2.57 (6H,m), 2.53-2.47 (2H, m), 2.38-2.27 (3H, m), 1.91-1.60 (9H, m).[M+H]⁺=606.5.

1-(butyryloxy)ethyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(Example 25, Compound 91)

Synthesis of chloro(phenyl)methyl carbonochloridate

To a solution of benzaldehyde (2.67 mL, 26.29 mmol) in diethyl ether (40mL) at −20° C. under argon was added triphosgene (8.61 g, 28.92 mmol)followed by pyridine (90.21 mL, 2.63 mmol). The reaction was allowed togradually warm to room temperature and stirred for 2 hours. The reactionwas filtered through celite and concentrated. The residue wasco-evaporated with diethylether (3×20 mL) to give chloro(phenyl)methylcarbonochloridate (5.44 g). This was used without further purification(contains ˜11% benzaldehyde).

Synthesis of chloro(phenyl)methyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

To a suspension of aripiprazole (1 g, 2.23 mmol) in2-methyltetrahydrofuran (20 mL) was added NaH (178 mg, 4.46 mmol). Thereaction was heated to reflux for 1.5 hours then cooled to roomtemperature. Chloro(phenyl)methyl carbonochloridate (1.37 g, 6.69 mmol)was then added and the reaction stirred overnight at room temperature.The reaction was cooled to 0° C., diluted with ethyl acetate (20 mL) andquenched with aqueous saturated NaHCO₃ (20 mL) solution. The reactionwas extracted with ethyl acetate (3×20 mL) and the combined organicswashed with brine (50 mL), then dried (MgSO₄) and concentrated to givechloro(phenyl)methyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(crude yield 2.10 g) as a 1:3 mixture of product/aripiprazole. Theproduct was taken onto the next step crude.

Synthesis of Compound 91

To a solution of chloro(phenyl)methyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(4.11 g, 6.66 mmol) in dimethyl formamide (40 mL) was added butyric acid(0.91 mL, 9.99 mmol) and cesium carbonate (1.63 g, 4.99 mmol). Thereaction was stirred at room temperature for 20 hours then diluted withethyl acetate (40 mL) and washed with 1:1 water/brine (3×50 mL). Theorganics were dried (MgSO₄) and concentrated. The crude product waspurified by column chromatography on silica eluting with 0.5% Et₃N/ethylacetate to give butyryloxy(phenyl)methyl7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate,Compound 91 (1.12 g). The material was determined to be 67% pure byLCMS.

¹H-NMR (300 MHz, CDCl₃) δ 7.66-7.57 (2H, m), 7.49-7.38 (3H, m),7.18-7.13 (2H, m), 7.07-7.04 (1H, m), 6.98-6.92 (1H, m), 6.73-6.61 (2H,m), 3.96-3.83 (2H, m), 3.11-3.00 (4H, m), 2.89-2.85 (2H, m), 2.74-2.63(6H, m), 2.57-2.51 (2H, m), 2.48-2.41 (2H, m), 1.81-1.60 (6H, m), 0.96(3H, dt).

[M+H]⁺=668.48.

Pharmacokinetic Evaluation in Rats Pharmacokinetic Evaluation ofProdrugs in Rats Following Oral Administration (PO)

Animals: Male Sprague-Dawley rats (Charles River Laboratories,Wilmington, Mass.) were obtained. Approximately 24 rats were used ineach study. Rats were approximately 350-375 g at time of arrival. Ratswere housed 2 per cage with ad libitum chow and water. Environmentalconditions in the housing room: 64-67° F., 30% to 70% relative humidity,and 12:12-h light:dark cycle. All experiments were approved by theinstitutional animal care and use committee.

Pharmacokinetics study: Rats were dosed 10 mg/kg (3.3 mL suspension) ofthe test compound (see Table E). Blood samples were collected from thejugular vein after brief anesthesia with Isoflurane. A 27½ G needle and1 cc syringe without an anticoagulant was used for the blood collection.Approximately 250 μL of whole blood was collected at each samplingtime-point of 15 and 30 minutes, and 1, 2, 4, 7 and 24 hours afteradministration. Once collected, whole blood was immediately transferredprechilled tubes containing EDTA, inverted 10-15 times and immediatelyplaced on ice. The tubes were centrifuged for 2 minutes at >14,000 g's(11500 RPMs using Eppendorf Centrifuge) at room temperature to separateplasma. Plasma samples were transferred to labeled plain tubes(MICROTAINER®) and stored frozen at <−70° C.

Data Analysis: Drug concentrations in plasma samples were analyzed byliquid chromatography-mass spectroscopy using appropriate parameters foreach compound. Half-life, volume of distribution, clearance, maximalconcentration, and AUC were calculated by using WinNonlin Version5.2_software (Pharsight, St. Louis, Mo.). Results are shown in TheFIGURE.

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A prodrug compound of Formula I, II or III:

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof; wherein A and B together with the —N(C═X)— or —(SO₂)N— to which they are attached forms a parent drug; X is —S— or —O—; R₁ is selected from —C(O)OR₂₀, —C(O)R₂₀, —C(O)NR₂₀R₂₁, —PO₃MY, —P(O)₂(OR₂₀)M and —P(O)(OR₂₀)(OR₂₁); wherein each R₂₀ and R₂₁ is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.
 2. (canceled)
 3. A compound of claim 1, wherein R₁ is selected from Table 1, 2, 3 or
 4. 4. A compound of claim 1 having the formula:

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof; wherein

represents a single or double bond; X and R₁ are as defined above; each X₁, X₂, and X₃ is independently selected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—, —C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—, —C(R₁₀)(R₁₁)═C(R₁₀)(R₁₁)—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; wherein each R₁₀ and R₁₁ is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R₁₀ and R₁₁ together with the atoms to which they are attached may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; and t is 0, 1, 2 or
 3. 5. A compound of claim 4 having the formula:

or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof; wherein

represents a single or double bond; X, X₁, X₂ and R₁ are as defined above; semicircle represents an optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl or aryl containing one, two or three rings; each F₁ and F₂ is independently selected from absent and R₅-A-Cy₁-B-D-; wherein, A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —S—, —O—, —S(O)—, —S(O)₂—, —S[C(R₃₀)(R₃₁)]_(u)—, —S(O)[C(R₃₀)(R₃₁)]_(u)—, —S(O)₂[C(R₃₀)(R₃₁)]_(u)—, —O[C(R₃₀)(R₃₁)]_(u)—, —N(R₃₀)—, —N(R₃₀)[C(R₃₁)(R₃₂)]_(u)—, —[C(R₃₀)(R₃₁)]_(u), —C(O)[C(R₃₀)(R₃₁)]_(u)—; wherein each u is independently 1, 2, 3, 4, 5, 6 or 7; Cy₁ is absent or an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; B is absent, or a linker; D is selected from absent, —O—, —NR₃₃, —C(R₃₄)(R₃₅)—, —S—, —S(O)—, —S(O)₂—, —C(O)—; each G₁ and G₂ is independently selected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —SC(R₄₀)(R₄₁)—, —S(O)C(R₄₀)(R₄₁)—, —S(O)₂C(R₄₀)(R₄₁)—, —C(O)—, —C(OR₄₀)(R₄₁)—, —OC(R₄₀)(R₄₁)—, —N(R₄₀)—, —C(R₄₀)═C(R₄₁)—, —N(R₄₀)—C(R₄₁)(R₄₂)—, —[C(R₄₀)(R₄₁)]_(U)—; each R₃, R₄, R₅, R₃₀, R₃₁, R₃₂R₃₃, R₃₄, R₃₅, R₄₀, R₄₁, and R₄₂ is independently selected from absent, hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, —C(O)R₁₀, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl; Alternatively, two R₃ groups together or two R₄ groups together or one R₃ group with one R₄ group together forms an optionally substituted ring; m and q are independently selected from 0, 1, and
 2. 6. A compound of claim 5, wherein R₅ is selected from:

wherein R₁₀₀ R₁₀₁, and R₁₀₃ are independently selected from hydrogen, halogen, optionally substituted C₁-C₈ alkyl, optionally substituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ alkoxy, optionally substituted C₁-C₈ alkylamino and optionally substituted C₁-C₈ aryl.
 7. A compound of claim 5, wherein Cy1 is selected from:


8. A compound of claim 5 having the formula:

wherein R₁, R₃, R₄, G₁, G₂, X, F₂, m and q are as defined above.
 9. A compound of claim 8 having the formula:

wherein R₁, R₃, F₂, and q are as defined above.
 10. A compound of claim 9 selected from Table IX-X, wherein R₁ is as defined above.
 11. (canceled)
 12. (canceled)
 13. A compound of claim 5 having the formula:

wherein R₁, R₃, R₄, X, F₁, G₁, G₂, m and q are as defined above.
 14. A compound of claim 13 having the formula:

wherein R₁, R₃, R₄, R₅, R₁₀, R₁₁, A, D, m, and q are as defined above; R₂ is selected from absent, hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionally substituted aliphatic, optionally substituted aryl or aryl or optionally substituted heterocyclyl; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; each G₃ and G₄ is independently selected from —N—, —C(R₁₀)—[C(R₁₀)(R₁₁)]_(a)—, wherein a is 0, 1 or 2; X₂₀ is —C(R₁₀)— or —N—; and p is selected 0, 1, 2 or
 3. 15. A compound of claim 14 having the formula:

wherein R₁, R₂, R₃, R₄, R₅, R₁₀, R₁₁, A, D, m, p and q are as defined above.
 16. A compound of claim 15 having the formula:

wherein R₁, is as defined above; and w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or
 11. 17. A compound of claim 15 having the formula:

wherein, X₁, R₁, R₂, R₃, R₅, A, B, D, G₃, G₄, p, q, R₁₀ and R₁₁ are as defined above.
 18. A compound of claim 17 having the formula:

wherein, X, R₁, R₂, D, r, R₁₀ and R₁₁ are as defined above.
 19. A compound of claim 18 having the formula:

wherein R₁, is as defined above.
 20. (canceled)
 21. (canceled)
 22. (canceled)
 23. (canceled)
 24. A compound of claim 13 selected from Table XI-XII wherein R₁ is as defined above.
 25. (canceled)
 26. (canceled)
 27. A compound of claim 24, selected from Tables A-F.
 28. A compound of claim 5, selected from Table VI-VII, wherein R₁ is as defined above.
 29. A compound of claim 1 having the formula:

wherein F₁ and R₁ are as defined above.
 30. A compound of claim 29 having the formula:

wherein R₁ is as defined above; Cy₂ is an optionally substituted heterocyclic ring; and X₅ is selected from absent, S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—, —C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—, —O[C(R₁₀)(R₁₁)]_(v)—, —O[C(R₁₀)(R₁₁)]_(v)O—, —S[C(R₁₀)(R₁₁)]_(v)O—, —NR₁₂[C(R₁₀)(R₁₁)]_(v)O—, —NR₁₂[C(R₁₀)(R₁₁)]_(v) S—, —S [C(R₁₀)(R₁₁)]_(v)—, —C(O)[C(R₁₀)(R₁₁)]_(v)—, and —C(R₁₀)(R₁₁)═C(R₁₀)(R₁₁)—; wherein v is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or
 10. 31. (canceled)
 32. (canceled)
 33. (canceled)
 34. (canceled)
 35. (canceled)
 36. (canceled)
 37. A compound of claim 1 having the Formula XXXIII, XXXIV, XXXV, XXXVI or XXXVII:

wherein, X, X₁, X₂, R₁₀₀, R₁₀₁, and R₁ are as defined above; X₁₀ is —S or —O.
 38. (canceled)
 39. A compound of claim 1 having the Formula XXXVIII or XXXIX:

wherein X, R₁, R₃, R₄, m and q are as defined above; X₁₁ is —N— or —C(R₁₀)—; X₁₂ is —C(O)—, —C(S)—, —C(R₁₀)(R₁₁)— or —C(R₁₀)(OR₁₁)—; and, X₁₃ is —O, —S, —N(R₁₀)(R₁₁), —OR₁₀.
 40. (canceled)
 41. A compound of claim 1 having the formula:

wherein R₁ is as defined above; each R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ is independently selected from absent, hydrogen, halogen, —OR₁₀, —SR₁₀, —NR₁₀R₁₁—, optionally substituted aliphatic, optionally substituted aryl or aryl or optionally substituted heterocyclyl; alternatively, two or more R₅₀, R₅₁, R₅₂, R₅₃, R₅₄ and R₅₅ together form an optionally substituted 3, 4, 5, 6 or 7 membered ring.
 42. (canceled)
 43. (canceled)
 44. A compound of claim 1 having the Formula XLII, XLIII or XLIV:

wherein R₁ R₁₀₀, R₁₀₁, X, X₁ and X₂ are as defined above; alternatively two R₁₀₀ and R₁₀₁ together with the atom to which they are attached form an optionally substituted 1, 2, 3, 4 or 5 membered ring.
 45. (canceled)
 46. (canceled)
 47. A compound of claim 1 having the Formula III, selected from Table III wherein R₁ is as defined above.
 48. A method of sustained delivery of a lactam, amide, imide, sulfonamide, carbamate, urea, benzamide, and acylaniline containing parent drug to a subject in need thereof, said method comprising the step of administering to the subject an effective amount of a prodrug compound produced by substituting a labile, hydrophobic prodrug moiety on the lactam, amide, imide, sulfonamide, carbamate, urea, benzamide, or acylaniline nitrogen atom or the carbonyl group.
 49. The method of claim 48, wherein the prodrug compound has decreased solubility compared to the parent drug when measured at room temperature in a pH 7.4 phosphate buffer.
 50. The method of claim 48, wherein the parent drug is represented by Formula LV or LVI:

and the prodrug is represented by Formula I, II or III:

wherein A and B together with the —N(C═X)— or —N═C—X— or —S(O)₂—N— they are attached forms a parent drug; X is —S— or —O—; R₁ is selected from —C(O)OR₂₀, —C(O)NR₂OR₂₁, —PO₃MY, —P(O)(OR₂₀)(OR₂₁), —C(O)[C(R_(A))(R_(B))O]_(z)—R₂₀, —C(O)O[C(R_(A))(R_(B))O]_(z)—R₂₀, —C(O)N(H)—[C(R_(A))(R_(B))O]_(z)—R₂₀; wherein z is 1, 2, 3, 4, 5, 6, or 7; wherein each R_(A) and R_(B) is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; each R₂₀ and R₂₁ is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.
 51. (canceled)
 52. (canceled)
 53. (canceled)
 54. (canceled)
 55. A compound of claim 1 selected from Tables A-F.
 56. (canceled)
 57. A compound of Formula I-XXXVII wherein R₁ is selected from —C(O)OR₂₀, —C(O)NR₂OR₂₁, —PO₃MY, —P(O)(OR₂₀)(OR₂₁), —C(O)[C(R_(A))(R_(B))O]_(z)—R₂₀, —C(O)O[C(R_(A))(R_(B))O]_(z)—R₂₀, —C(O)N(H)-[C(R_(A))(R_(B))O]_(z)—R₂₀; wherein z is 1, 2, 3, 4, 5, 6, or 7; wherein each R_(A) and R_(B) is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; each R₂₀ and R₂₁ is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation.
 58. The compound of claim 57, wherein R₂₀ is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aliphatic and substituted aliphatic.
 59. The compound of claim 57, wherein R₁ is selected from —C(O)O—CH₂—OC(O)R₂₁ or —C(O)NH—CH₂—OC(O)R₂₁ or —C(O)O—CH₂—OC(O)N(R₂₁)₂.
 60. The compound of claim 57, wherein R₁ is selected from —C(O)O—CH(CH₃)—OC(O)R₂₁ or —C(O)NH—CH(CH₃)—OC(O)R₂₁ or —C(O)O—CH(CH₃)—OC(O)N(R₂₁)₂.
 61. The compound of claim 57, wherein R₁ is selected from —C(O)O—CH(C₆H₅)—OC(O)R₂₁ or —C(O)NH—CH(C₆H₅)—OC(O)R₂₁ or —C(O)O—CH(C₆H₅)—O(O)N(R₂₁)₂. 